The class of polyketides known as epothilones has emerged as a source of potentially therapeutic compounds having modes of action similar to paclitaxel (Bollag, et al. 1995; Service 1996; Winkler and Axelsen 1996; Bollag 1997; Cowden and Paterson 1997). Interest in the epothilones and epothilone analogs has grown with the observations that certain epothilones are active against tumors that have developed resistance to paclitaxel (Harris, et al. 1999a) as well as reduced potential for undesirable side-effects (Muhlradt and Sasse 1997). Among the epothilones and epothilone analogs being investigated for therapeutic efficacy are epothilone B 1 (Oza, et al. 2000) and the semi-synthetic epothilone B analogs, BMS-247550 2, also known as “azaepothilone B” (Colevas, et al. 2001; Lee, et al. 2001; McDaid, et al. 2002; Yamaguchi, et al. 2002), and BMS-310705 3.

Desoxyepothilone B 4, also known as “epothilone D” is another epothilone derivative having promising anti-tumor properties viz. paclitaxel that is being investigated for therapeutic efficacy (Su, et al. 1997; Chou, et al. 1998a; Chou, et al. 1998b; Harris, et al. 1999b; Chou, et al. 2001; Danishefsky, et al. 2001b; Martin and Thomas 2001; Danishefsky, et al. 2002). This compound has also demonstrated less toxicity than epothilones having 12,13-epoxides, such as epothilone B or BMS-247550, presumably due to the lack of the highly reactive epoxide moiety.

Generally, pharmacologists and physicians prefer therapeutic formulations to have good oral availability to enhance patient compliance and ease of administration (DeMario and Ratain 1998). Formulations showing oral activity in mice have been described for BMS-247550 and BMS-310705 (Lee 2002a; b); however, these compounds lack the structural combination of a lactone oxygen and olefin found with epothilone D.
A single report of a polyethylene glycol-400:ethanol (10:1) formulation of epothilone D delivered orally to one mouse (at a dose of 50 mg/kg) showed no discernable effect on tumor size (Chou, et al. 1998b). Unfortunately, epothilone D has poor aqueous solubility; and current epothilone D formulations include a castor oil derivative solubilizing agent sold under the trade name CREMOPHOR® (BASF Aktiengesellschaft) to enhance solubility. These formulations are suitable only for intravenous delivery. While current epothilone D formulations are acceptable for clinical and therapeutic use, CREMOPHOR® has been associated with patient discomfort and toxicity. CREMAPHOR®-free formulations of epothilone B for intravenous delivery have been described (Van Hoogevest 1999). Therefore, it would be preferable to provide enhanced formulations of epothilone D that do not require CREMOPHOR® and, still more preferably, that can be delivered orally.